Rational Design of Pharmaceutical Salt Formulations by Understanding the Mechanism of Disproportionation
Salt forms of the active pharmaceutical ingredient (API) are commonly encountered in the pharmaceutical industry. About half of marketed pharmaceutical products contain the salt form of the API. Salt disproportionation, where the salt converts to the free form, is an important concern for pharmaceutical products containing the salt form of a drug. This is because conversion of the salt to the free form decreases the solubility and/or alters the reactivity, potentially resulting in a decrease in product quality. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties and crystal structure of the salt on the disproportionation reaction is unknown. In this study, by utilizing various model salts of weakly basic compounds, we have shown how differences in both solid forms, as well as the crystal structure of salt in general can led to differences in its disproportionation. The results of these studies indicated that the salts structures involving intermediate water molecules as a bridge between API and counterion are resistant to disproportionation. Salts having a crystalline arrangement where the salt bridge is shielded or those forming dual salt bridges are also shown to stable against disproportionation. On the other hand, amorphous salts which lack long-range ordered molecular packing are shown to highly prone to disproportionation. By understanding the correlation of solid form, crystal structure, and excipient properties to disproportionation, we can rationally design stable salt formulations.
Taylor, Purdue University.
Physical chemistry|Pharmaceutical sciences
Off-Campus Purdue Users:
To access this dissertation, please log in to our